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Background: To study the neuro-ophthalmologic characteristics of patients with the visual variant of Creuztfeldt-Jakob disease (CJD) predominantly affecting the occipital and parietal lobes, known as the Heidenhain variant (HvCJD). The initial symptoms and findings may overlap with other posterior cerebral degenerative disorders. We reviewed our experience with HvCJD including clinical course and results of neuroimaging, electroencephalography (EEG), and cerebrospinal fluid (CSF) studies. Neuropathological postmortem findings were reviewed when available to confirm the clinical impression.

Methods: Retrospective study of HvCJD patients examined in the past 15 years at a single tertiary referral university hospital. Rapid rate of visual and neurological deterioration and abnormal diffusion-weighted imaging (DWI) were characteristic for HvCJD.

Results: Three patients displayed abnormalities in DWI, EEG, and CSF and had rapid clinical progression, leading to a clinical diagnosis of HvCJD. None underwent diagnostic cerebral biopsy. In 2 patients, the diagnosis of sporadic CJD was confirmed by postmortem neuropathologic, immunohistochemical, and genetic studies.

Conclusions: The gold standard for establishing the diagnosis of HvCJD is based on the characteristic histopathologic findings and molecular confirmation. Concern with potential iatrogenic CJD, related to surgical instrumentation or operating room prion contamination, has limited the availability of confirmatory brain biopsy. Our case series illustrates how the combination of clinical neuroimaging and EEG studies and 14:3:3 protein and other neuronal protein marker levels can lead to the diagnosis of HvCJD. Immunohistochemical analysis and genetic testing at a specialized prion research center will assist in identifying the sporadic variant and genetic forms of CJD.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www.jneuro-ophthalmology.com).

John Farrel, MD, from the Department of Medicine, Division of Infectious Diseases consulted in Case 1.

Introduction

Posterior cortical degeneration (PCD) is the final common outcome from myriad etiologies with differing pathophysiologic mechanisms. Although several different histological subtypes have been identified, the essential feature of PCD is neuronal degeneration centered in the occipital, posterior temporal, and parietal lobes. The initial clinical manifestations of PCD suggest topographic localization but do not provide etiologic specificity.

The Heidenhain variant of Creutzfeldt-Jakob disease (HvCJD) is characterized by occipital and posterior parieto-temporal cortex neuronal loss induced by the mutant prion protein PrPSC. HvCJD is one cause of PCD, which is typically difficult to diagnose, rapidly progressive and accounts for approximately one-third of all Creuztfeldt-Jakob disease (CJD) cases (1–9).

METHODS

Three patients with HvCJD evaluated at the University of Illinois between 1998 and 2012 were included in our study. The institutional review board determined that this project did not meet the definition of human subject research according to federal regulations, given that all 3 patients died before the initiation of this retrospective investigation.

Concern about instrument and/or surgical suite contamination as possible sources of iatrogenic CJD (10) obstructed acquisition of a diagnostic brain biopsy at our institution. We pursued alternative diagnostic options. Elevation of the 14:3:3 and other neuronal proteins as a CJD marker could lead to a misdiagnosis of HvCJD in PCD patients with or without associated dementia. We applied diagnostic criteria proposed by Kropp et al (6) that are endorsed by the World Health Organization and the American Academy of Neurology 14:3:3 protein evidence-based guideline (2). These criteria include disease duration less than 2 years and a compatible aggregate of clinical magnetic resonance imaging (MRI), serial electroencephalography (EEG) data, and elevated cerebrospinal fluid (CSF) 14:3:3 and/or other neuronal proteins (2–5). Postmortem tissue examination with immunohistochemical staining and genetic testing confirmed sporadic CJD in 2 of our patients.

Case Reports

All patients were referred to our Neuro-Ophthalmology Unit with visual disturbances. One patient was transferred from an outside facility with progressive cortical blindness and advanced encephalopathy. The other 2 patients presented at an earlier stage of disease: 1 with an isolated visual field defect and 1 with a visual field defect, dyschromatopsia, and visual hallucinations. These latter 2 patients developed rapid neurological deterioration occurring over the ensuing 4 weeks.

Case 1

A 73-year-old Caucasian cattle farmer with diabetes mellitus, hypertension, and essential tremor noted episodic painless diplopia and blurry vision. He had previously received panretinal photocoagulation for diabetic retinopathy in both eyes. At that time, his symptoms were believed due to the diabetic complications of retinopathy and ocular motor paresis. Three weeks later, he reported “progressive fading vision” and that he “could not talk right.” Computed tomography and MRI of the brain were reported to be normal. Over the next 2 weeks, his visual loss progressed. He could not visually recognize objects or people, although he could recognize them by touch or hearing their voices.

We initially evaluated the patient 2 months after the onset of symptoms. At that time, he could not perform any activities of daily living. His visual acuity could not be assessed. Pupils reacted sluggishly to light and optokinetic response was absent. Ophthalmoscopic examination showed bilateral optic disc pallor and evidence of panretinal photocoagulation. He had no family history of dementia or medical procedures that would have placed him at risk for iatrogenic CJD. During his hospitalization, the patient slept most of the time, with weak arousals, and developed startle myoclonus.

MRI of the brain showed ribbon-like gyriform hyperintensities in the occipital lobes due to restricted diffusion. No abnormalities were noted in the basal ganglia. He had 2 EEGs: the first showed diffuse slowing and intermittent generalized spike and wave complexes. Three days later, a second EEG showed generalized triphasic wave complexes at a 1 Hz frequency (Fig. 1). Laboratory testing showed low serum thiamine and vitamin B12 levels. CSF 14:3:3 and neuron-specific enolase levels were increased. Following an advanced directive, his family elected to withdraw care. Ten weeks after the onset of visual symptoms, he expired. Examination before death in the hospital revealed a mute, akinetic cortically blind patient.

Case 2

A 74-year-old Caucasian woman with chronic bronchitis and bilateral hearing loss secondary to otosclerosis complained of blurred vision and difficulty with balance. Visual acuity was 20/25 in each eye with reduced color vision bilaterally. Pupillary reactions and eye movement were normal, and the fundi were unremarkable. Automated visual field testing demonstrated a left homonymous hemianopia (Fig. 2). Neurological examination including vestibular testing was normal.

EEG showed focal slowing in the right parietal region, and brain MRI revealed increased signal in the cortical gyri of the right tempo-parietal junction. No abnormalities were noted in the cerebellum or basal ganglia.

Two weeks later, neuropsychometric testing showed deficits involving multiple cognitive domains. The patient had short- and long-term memory loss and impairment of orientation, attention, and concentration. She had decreased ability to learn new information, impaired verbal comprehension and arithmetic skills, and decreased left sensory perception. She had bilateral visual field defects, difficulty with left hand-eye coordination, spasm of fixation, and optic ataxia. One week later, she was still able to walk without assistance but progressive difficulty with her vision rendered her unable to get around her home or feed herself without assistance. On examination, she was cortically blind.

Six weeks after initial evaluation, the patient was admitted to hospital because she was unable to care for herself. She was in a mute akinetic state with reactive pupils but without response to visual threat. There was left beat nystagmus in primary gaze alternating with periods of left gaze deviation that could be overcome with head turn (See Supplemental Digital Content, Video, http://links.lww.com/WNO/A73). A few days later, she developed startle and spontaneous myoclonus. EEG showed 1-Hz periodic sharp wave discharges preceding the myoclonus, characteristic of CJD. MRI revealed right temporo-parietal gyriform hyperintensity on T2 and fluid-attenuated inversion recovery image (FLAIR) sequences, CSF demonstrated elevated protein of 75 mg/dL (normal: 35–45 mg/dL) but no other abnormalities. The 14:3:3 protein was not tested. She was discharged home with hospice care and died about 12 weeks after the onset of her first visual symptoms. An autopsy was not performed.

Case 3

A 77-year-old Caucasian woman, retired surgical nurse, with hypertension, diabetes mellitus, congestive heart failure, atrial fibrillation, ulcerative colitis, and osteoporosis reported a 2-week history of multicolored visual hallucinations and intermittent distortion of images. Visual acuity was 20/60, right eye, and 20/100, left eye. Pupils reacted normally to light and accommodation. She could not read the Ishihara color plates but was able to name individual colors. A right homonymous hemianopia was detected by confrontation technique but the patient could not perform formal visual field testing. Ophthalmoscopic and biomicroscopic examinations were normal.

There was diffuse slowing of background activity on EEG and a visual evoked potential testing showed prolonged P100 latencies. There was an area of increased gyriform signal in the left striate cortex on brain MRI without abnormalities in the basal ganglia or cerebellum (Fig. 3). Single-photon emission computed tomography (SPECT) scan showed decreased perfusion in the left posterior parietal-occipital region.

Within 2 weeks of presentation, the patient developed visual agnosia, prosopagnosia, impaired short-term memory, speech problems, confusion, and mild right-sided clumsiness. On admission, the Folstein Mini Mental Status Examination score was 4/30 (normal: 30/30). She was still able to recite the Lord's Prayer with no mistakes. She had a 2-fold increase in CSF 14:3:3, and neuronal-specific enolase level was also increased (82.5 ng/mL; normal: <35 ng/mL). A follow-up examination 7 weeks after initial presentation demonstrated startle myoclonus. She was unresponsive but arousable and had a right hemiparesis and right Babinski sign. She died approximately 8 weeks after the onset of her visual symptoms.

Autopsy showed spongiform encephalopathy, neuronal loss, and gliosis, affecting primarily the occipital cortex and cerebellum (Fig. 4). These findings were consistent with the diagnosis of CJD. Western blot prion (PrP) gene and immunohistochemical examination of the brain confirmed the diagnosis of sporadic CJD with homozygozity for methionine in codon 129. Given her occupation history as a surgical nurse for 50 years, there was an investigation into the possibility of an iatrogenic mechanism, but no exposure link to a CJD source was identified.

DISCUSSION

In 1998, Benson et al (11) described PCD as an unusual neurodegenerative disorder involving the posterior parietal and occipital lobes. Neuropathologic findings in PCD include senile plaques and neurofibrillary tangles, typical for Alzheimer disease in the majority of cases (7–9). Less frequently, subcortical gliosis as a variant of Pick disease and spongiform changes, neuronal loss and gliosis due to prion infection were reported (9). However, epidemiologic data are lacking. Clinical findings in PCD and HvCJD include combinations of visual field defects, cortical blindness, dyschromatopsia, visual agnosia, alexia, prosopagnosia, palinopsia, optical anosognosia, Balint and Gertsmann syndrome (12–16).

Between 1998 and 2012, we evaluated 10 patients with PCD; 3 had sporadic HvCJD who were followed until their death. We are uncertain about the etiology in the remaining 7 patients who developed either a slowly progressive dementia (evolving over several years) and are still alive or were lost to follow-up.

The largest published series of the HvCJD included 34 pathologically confirmed cases over a 51-month period (6). This study from the University of Göttingen in Germany is the geographic base of the “German National Creutzfeldt-Jakob Disease Surveillance Study.” Clinical findings were available in 25 cases and consisted of a combination of visual loss and higher visual deficits as found in previous studies. The rate of neurological deterioration was faster in the HvCJD group compared with other CJD variants and did not correlate with location or extent of neuropathologic findings. Homozygosis for methionine in codon 129, identified in 2 of our patients, was noted as a possible genetic indicator of an aggressive clinical course.

We evaluated our patients by applying the diagnostic criteria used by Kropp et al (6) and endorsed by the World Health Organization (Table 1). Neuroimaging findings showed subtle increased intensity in the parieto-occipital region on T2 and FLAIR images only in case 2. Yet all 3 patients had striking visual deficits on examination. Therefore, HvCJD should be considered in any patient with visual field loss and a normal MRI or when imaging abnormalities fail to explain the clinical findings (15). Our imaging protocol included diffusion-weighted imaging (DWI) sequences (12,16). Restricted diffusion involving the gyri of the parieto-occipital cortex was observed in 2 of our cases (Fig. 3). The third patient (Case 2) was evaluated before the incorporation of DWI sequences in the MRI protocol at our institution. DWI was the most helpful ancillary test supporting the diagnosis of HvCJD, and to our knowledge, other PCD variants usually are not associated with DWI changes.

Initial EEG results showed nonspecific focal or generalized slowing, but follow-up EEG showed periodic sharp waves (Fig. 2) characteristic of CJD in later stages, correlating with the presence of myoclonus. SPECT scanning confirmed occipital hypoperfusion in one of our cases and should be part of PCD evaluation. SPECT largely has been replaced by PET that demonstrates focal cerebral hypometabolism in PCD (13,17).

An important characteristic observation suggesting HvCJD in our patients was rapid clinical deterioration. The initial HvCJD diagnosis in Case 1 was supported by progressive neurological deterioration over 10 weeks after the onset of visual symptoms. Our other 2 patients were evaluated at an earlier stage of disease and were scheduled for additional testing over several days. Both patients failed to keep their 2-week follow-up appointments, and contact with their families revealed that they experienced rapid neurological deterioration with inability to perform activities of daily living. This prompted us to perform house calls to complete neurological evaluation and discussion with the family.

Markers of massive neuronal loss (14:3:3 protein and neuronal-specific enolase) were elevated in 2 of our cases. These markers are deemed highly specific and sensitive (1). Their value must be interpreted with caution in individual cases, as increased neuronal protein levels (false positives) may be found in other rapidly progressive dementias and potential PCD mimics including autoimmune and paraneoplastic encephalitis, nonconvulsive status epilepticus, intravascular lymphoma, and vasculitis (2,5).

Although characteristic histopathology of CJD remains the gold standard in establishing the diagnosis, the risk of instrument or surgical suite prion contamination during brain biopsy has limited the availability of brain biopsy (10). Until a specific serum or CSF prion marker is available, the premortem diagnosis of HvCJD in a patient with PCD continues to rely on close clinical monitoring, neuroimaging testing, serial EEG, and elevated CSF markers (18,19). We strongly recommend that specimens be sent to the National Prion Research Center at Case Western Reserve University in Cleveland, OH, and similar prion research centers for confirmatory, cerebral histopathology, immunohistochemical staining of abnormal protease-resistant prion protein, and genetic testing. This testing protocol establishes the diagnosis of sporadic, variant, and genetic forms of CJD and hopefully will prevent delay in establishing the correct diagnosis (20).

In vitro, anti-prion agents have been found effective in controlling prion growth and progression. Unfortunately, these agents have failed to cure or slow CJD infection in humans (21–23).